EP1360184A1 - Piperidinderivate als neurokinin?1?antagonisten - Google Patents

Piperidinderivate als neurokinin?1?antagonisten

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Publication number
EP1360184A1
EP1360184A1 EP20020710043 EP02710043A EP1360184A1 EP 1360184 A1 EP1360184 A1 EP 1360184A1 EP 20020710043 EP20020710043 EP 20020710043 EP 02710043 A EP02710043 A EP 02710043A EP 1360184 A1 EP1360184 A1 EP 1360184A1
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EP
European Patent Office
Prior art keywords
phenyl
trifluoromethyl
bis
piperidin
methanone
Prior art date
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Granted
Application number
EP20020710043
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English (en)
French (fr)
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EP1360184B1 (de
Inventor
Sabine Kolczewski
Stephan Roever
Patrick Schnider
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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Priority to DK02710043T priority Critical patent/DK1360184T3/da
Priority to EP02710043A priority patent/EP1360184B1/de
Publication of EP1360184A1 publication Critical patent/EP1360184A1/de
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to compounds ofthe general formula
  • R 1 a is phenyl, unsubstituted or substituted by one or more substituents selected from the group R 1 consisting of
  • R ⁇ is independently from "m” hydrogen, halogen, lower alkyl, -NH-(CH 2 ) ⁇ -O-lower alkyl, pyrrolidinyl or morpholinyl;
  • R /R are independently from each other trifiuoromefhyl or halogen
  • R is hydrogen or lower alkyl and may be the same or different in case of R 2 ;
  • n 1, 2, 3 or 4;
  • n 0, 1 or 2;
  • R is lower alkyl, m is 0, 1 or 2, R", R and R have the significances given above, or to
  • R , 1" , D R2 , r R)3 and R have the significances given above, or to
  • R , 1'" , R n 2 , ⁇ R3 and R have the significances given above, or to
  • R > 2 , ⁇ R3 ' a curatnd, R ⁇ 4 are described above and m is 0, 1 or 2.
  • R 1 is phenyl, unsubstituted or substituted by one or two substituents, selected from the group R 1 , consisting of
  • - halogen or is thiomorpholinyl, 1-oxo-thiomorpholinyl or 1,1-dioxothiomorpholinyl;
  • R 2 is hydrogen, halogen, lower alkyl, -NH-(CH 2 ) n -O-lower alkyl, pyrrolidinyl or morholinyl;
  • R is hydrogen or lower alkyl and may be the same or different in case of R 2 ; and n is 1, 2, 3 or 4;
  • the compounds of formula I and their salts are characterized by valuable therapeutic properties. It has been surprisingly found that the compounds ofthe present invention are antagonists ofthe Neurokinin 1 (NK-1, substance P) receptor.
  • NK-1 Neurokinin 1
  • Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue.
  • the receptor for substance P is a member ofthe superfamily of G protein-coupled receptors.
  • the neuropeptide receptor for substance P (NK-1) is widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes.
  • the central and peripheral actions ofthe mammalian tachykinin substance P have been associated with numerous inflammatory conditions including migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease as well as mediation ofthe emetic reflex and the modulation of central nervous system (CNS) disorders such as Parkinson's disease (Neurosci. Res., 1996, 7, 187-214), anxiety (Can. J.
  • tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases ofthe gut including ulcerative colitis and Crohn's disease, ocular injury and ocular inflammatory diseases reviewed in "Tachykinin Receptor and Tachykinin Receptor Antagonists", J. Auton. Pharmacol, 13, 23-93, 1993.
  • Neurokinin 1 receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinin, in particular substance P.
  • Examples of conditions in which substance P has been implicated include disorders ofthe central nervous system such as anxiety, depression and psychosis (WO 95/16679, WO 95/18124 and WO 95/23798).
  • the neurokinin- 1 receptor antagonists are further useful for the treatment of motion sickness and for treatment induced vomiting.
  • the New England Journal of Medicine, Vol. 340, No. 3 190-195, 1999 has been described the reduction of cisplatin-induced emesis by a selective neurokinin-1- receptor antagonist.
  • US 5,972,938 describes a method for treating a psychoimmunologic or a psychosomatic disorder by administration of a tachykinin receptor, such as NK-1 receptor antagonist.
  • neurokinin 1 receptor antagonists for the treatment of certain forms of urinary incontinence is further described in "Neuropeptides, 32(1), 1-49, (1998)” and "Eur. J. Pharmacol., 383(3), 297-303, (1999)".
  • the compounds of formula I can also be used in form of their prodrugs.
  • examples are esters,- N-oxides, phosphate esters, glycoamide esters, glyceride conjugates and the like.
  • the prodrugs may add to the value ofthe present compounds advantages in adsorption, pharmacokinetics in distribution and transport to the brain.
  • NIC! receptor antagonists have been reported to have also a beneficial effect in the therapy of traumatic brain injury (oral disclosure by Prof. Nimmo at the International Tachykinin Conference 2000 in La Grande Motte, France, October 17-20, 2000 with the title "Neurokinin 1 (NK-1) Receptor Antagonists Improve the Neurological Outcome Following Traumatic Brain Injury” (Authors: A.J. Nimmo, C.J. Bennett, X.Hu, I. Cernak, R. Vink)."
  • Objects ofthe present invention are the compounds of formula I and pharmaceutically acceptable salts thereof, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture as well as the use ofthe above- mentioned compounds in the control or prevention of illnesses, especially of illnesses and disorders ofthe kind referred to earlier or in the manufacture of corresponding medicaments.
  • Objects of the present invention are all racemic compounds of formula I, including their corresponding enantiomers. Most of the enantiomers have been separated from their corresponding racemic compounds. It has been shown that the corresponding enantiomers are more active in the test for NK-1 binding as described below.
  • the preferred stereochemical position is the cis-position.
  • the most preferred indications in accordance with the present invention are those, which include disorders ofthe central nervous system, for example the treatment or prevention of certain depressive disorders or emesis by the administration of NK-1 receptor antagonists.
  • a major depressive episode has been defined as being a period of at least two weeks during which, for most ofthe day and nearly every day, there is either depressed mood or the loss of interest or pleasure in all, or nearly all activities.
  • lower alkyl denotes a straight- or branched- chain alkyl group containing from 1-7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like.
  • Preferred lower alkyl groups are groups with 1-4 carbon atoms.
  • lower alkoxy denotes a group wherein the alkyl residues are as defined above, and which is attached via an oxygen atom.
  • halogen denotes chlorine, iodine, fluorine and bromine.
  • cycloalkyl denotes a saturated carbocyclic group, containing 3-6 carbon atoms.
  • pharmaceutically acceptable acid addition salts embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
  • R 1 is hydrogen, bromo, morpholinyl, 4-methyl-piperazinyl or -NH(CH 2 ) 2 OCH 3 , for example the following compounds:
  • R 2 is hydrogen, fluoro or chloro.
  • R 2 is hydrogen, fluoro or chloro.
  • examples of such compounds are: rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[3-(4-chloro-phenyl)-4-morpholin-4-yl- piperidin-1-yl] -methanone, rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(4-morpholin-4-yl-3-phenyl-piperidin-l-yl)- methanone, rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[3-(4-fluoro-phenyl)-4-morpholin-4-yl- piperidin-1-yl] -methanone or
  • R 1 is hydrogen, methyl, -C(O)CF 3 , -(CH 2 ) 2 OH, -CH 2 C(O)N(CH 3 ) 2) CH 2 -cyclopropyl, benzyl, -C(O)-cyclopropyl, -C(O)-morpholinyl, pyrazinyl, cyclopropyl or -CH 2 CONHC 6 H 3 (CH 3 ) 2 , -CH 2 CONHC 6 H 4 F, -C(O)CH 2 -phenyl, and R 2 is hydrogen, methyl, chloro or fluoro. Examples of such compounds are:
  • R 1 is phenyl, optionally substituted by halogen
  • R 2 , R 3 and R have the significances given above, hal is halogen and m is 0, 1 or 2, or
  • R, R , R , R and m have the significances given above, or
  • R , 1" , ⁇ R2 " , ⁇ R3 , r R > i and m have the significances given above, or
  • R , R , R , R and m have the significances given above, or
  • R 1 , R 2 , R 3 , R 4 and m have the significances given above, or
  • R ,2 , ⁇ R , ⁇ R4 and m have the significances given above, or
  • R 1 is piperazinyl, optionally substituted by lower alkyl, morpholinyl, -NH-phenyl, pyrrolidinyl, -NH(CH 2 ) n -0 -lower alkyl, -NR 2) -NH(CH 2 ) n -cycloalkyl or -NH(CH 2 ) n -NR 2 , and the definitions of R 2 , R 3 and R 4 are given above, or
  • R is -(CH 2 ) n -cycloalkyl, and R 2 , ⁇ R>3 ⁇ , r R> and m are described above, or
  • R 1 is phenyl, optionally substituted by halogen, R 2 , R 3 and R 4 are described above, m is 0, 1 or 2 and hal is chloro or bromo.
  • R 2 is described above, m is 0, 1 or 2 and R 1 ' is piperazinyl, optionally substituted by lower alkyl, or is morpholinyl, -NH-phenyl, pyrrolidinyl, -NH(CH 2 ) n -O-lower alkyl, -NR 2 , -NH(CH 2 ) n -cycloalkyl or -NH(CH 2 ) n -NR 2 .
  • Hal is bromo or chloro and m is 0, 1 or 2.
  • Compounds of formula 1A1 can be obtained by amination of aromatic chlorides or bromides of formula V using an amine of formula VI, like morpholine or N- methylpiperazine, and sodium tert-butoxide, a catalyst like tris(dibenzylideneacetone)dipalladium(0) and a ligand like rac-2,2'- bis(diphenylphosphino)-l,l'-binaphthyl or biphenyl-2-yl-dicyclohexyl-phosphane in an inert solvent like toluene.
  • the method is described in detail in S. Buchwald et al, /. Am. Chem. Soc. 1996, 118, 7215-7218 and /. Am. Chem. Soc. 1998, 120, 9722-9723.
  • R 1 , R 2 , R 3 and R and m have the significances given above and hal is chloro or bromo.
  • Compounds of formula IC can be obtained by
  • R 2 , R 3 and R have the significances given above and m is 1 or 2.
  • R 2 , R " and R have the significances given above and R 5 may be, for example, -(CH 2 ) n -cycloalkyl.
  • Hal is chloro or bromo.
  • Ethers of formula IE2 can be obtained by treating an alcohol of formula IE1 with a base like sodium hydride and an alkylating agent like an alkyl bromide or alkyl chloride of formula VIII in an inert solvent like dimethylformamide.
  • R"" is morpholinyl, -NR 2 , -NR-cycloalkyl, -NR-C(O)-cycloalkyl, -NR-C(O)-phenyl or -NR-C(O)-(CH 2 ) n -phenyl, R, R 2 , R' ⁇ R 4 and m have the significances given above and hal is preferably fluoro.
  • Ketone derivatives of formula IE3 can be obtained by Swern oxidation of an alcohol of formula IE1 by methods known in the art.
  • Compounds of formula IE4 can be obtained by treating a ketone of formula IE3 with, for example, diethylamino sulfurtrifluoride, in an inert solvent like methylene chloride.
  • Compounds of formula IE5 can be obtained by reductive amination by treating a ketone of formula IE3 with, for example, titanium(IV) isopropoxide and a mixture of ammonium chloride and triethylamine or a primary or secondary amine and consecutively with sodium borohydride or sodium cyanoborohydride or by substitution of an alcohol IE1 with the sequence (a) reaction with methanesulfonyl chloride and triethylamine in dichloromethane, (b) treatment with sodium azide in dimethylformamide (c), reduction of the intermediate azide with hydrogen and a palladium catalyst (d) alkylation or acylation ofthe free amine.
  • a ketone of formula IE3 with, for example, titanium(IV) isopropoxide and a mixture of ammonium chloride and triethylamine or a primary or secondary amine and consecutively with sodium borohydride or sodium cyanoborohydride or by substitution of an alcohol IE1 with the
  • R'" is NR 2 , -N(cycloalkyl) 2 , -N[(CH 2 ) n -cycloalkyl] 2 or -NR-C(O)-cycloalkyl
  • R, R 2 , R 3 , R 4 and m have the significances given above and hal is preferably fluoro.
  • the salt formation is effected at room temperature in accordance with methods which are known per se and which are familiar to any person skilled in the art. Not only salts with inorganic acids, but also salts with organic acids come into consideration. Hydrochlorides, hydrobromides, sulphates, nitrates, citrates, acetates, maleates, succinates, methane-sulphonates, p-toluenesulphonates and the like are examples of such salts. As mentioned earlier, the compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. It has been found that the compounds ofthe present invention are antagonists ofthe Neurokinin 1 (NK-1, substance P) receptor.
  • NK-1 Neurokinin 1
  • Binding assays were performed in HEPES buffer (50 mM, pH 7.4) containing BSA (0.04 %) leupeptin (8 ⁇ g / ml), MnCl (3 mM) and phosphoramidon (2 ⁇ M). Binding assays consisted of 250 ⁇ l of membrane suspension (1.25xl0 5 cells / assay tube), 0.125 ⁇ l of buffer of displacing agent and 125 ⁇ l of [ ⁇ ] substance P.
  • Displacement curves were determined with at least seven concentrations ofthe compound.
  • the assay tubes were incubated for 60 min at room temperature after which time the tube contents were rapidly filtered under vacuum through GF/C filters presoaked for 60 min with PEI (0.3%) with 2 x 2 ml washes of HEPES buffer (50 mM, pH 7.4). The radioactivity retained on the filters was measured by scintillation counting. All assays were performed in triplicate in at least 2 separate experiments.
  • the affinity to the NK-1 receptor is in the scope of 6.70 - 9.44 for the compounds of formula I of the present invention.
  • the preferred compounds with a pKi >8.5 are shown in the table below:
  • the compounds of formula I as well as their pharmaceutically usable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical preparations.
  • the pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions.
  • the administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
  • the compounds of formula I and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients e.g. for tablets, dragees and hard gelatine capsules.
  • Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semi- solid and liquid polyols etc.
  • Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc.
  • Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc.
  • Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc.
  • the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • the dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case.
  • a daily dosage of about 10 to 1000 mg per person of a compound of general formula I should be appropriate, although the above upper limit can also be exceeded when necessary.
  • the crude intermediate was dissolved in dichloromethane (100 mL) and triethylamine (7.25 mL, 51.7 mmol) and 3,5-bistrifluoromethyl-benzoyl chloride (2.06 mL, 11.4 mmol) were added.
  • the reaction mixture was stirred at room temperature overnight and than diluted with 100 mL water.
  • the organic phase was separated and the aqueous layer was extracted twice with 100 mL dichloromethane. Organic phases were pooled, dried with magnesium sulfate and evaporated.
  • the crude intermediate was dissolved in dichloromethane (30 mL) and triethylamine (1.22 mL, 8.75 mmol) and 3,5-bistrifluoromethyl-benzoyl chloride (0.35 mL, 1.93 mmol) were added.
  • the reaction mixture was stirred at room temperature overnight and than diluted with 50 mL water.
  • the organic phase was separated and the aqueous layer was extracted twice with 50 mL dichloromethane. Organic phases were pooled, dried with magnesium sulfate and evaporated.
  • the intermediate azide (704 mg, 1.30 mmol) was dissolved in methanol (50 mL) and palladium on charcoal (10%, 138 mg) was added. After stirring in a hydrogen atmosphere (1 bar) at room temperature overnight the mixture was filtered and the solvent was evaporated. The crude amine (490 mg, 73%) was used for the next step without further purification.
  • the intermediate free piperazine was dissolved in N,N-dimethylformamide (10 mL) and potassium carbonate (166 mg, 1.20 mmol) and bromomethylcyclopropane (0.043 mL, 0.440 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 3 hours. Water (30 mL) was added and the mixture was extracted three times with 50 mL tert-butyl methylether. Organic phases were pooled, dried with magnesium sulfate and evaporated.
  • the crude intermediate was dissolved in dichloromethane (50 mL) and triethylamine (1.99 mL, 14.2 mmol) and 3,5-bistrifluoromethyl-benzoyl chloride (0.643 mL, 3.55 mmol) were added.
  • the reaction mixture was stirred at room temperature overnight and than diluted with 50 mL water.
  • the organic phase was separated and the aqueous layer was extracted twice with 50 mL dichloromethane. Organic phases were pooled, dried with magnesium sulfate and evaporated.
  • the intermediate free piperazine was dissolved in methanol (10 mL) and acetic acid (0.109 mL, 1.90 mmol), powdered molecular sieves (1 small spatula), [(1- ethoxycyclopropyl)oxy]trimethylsilane (0.152 mL, 0.761 mmol) and sodium cyanoborohydride (36 mg, 0.571 mmol) were added.
  • the reaction mixture refluxed for 8 hours, cooled and filtered. 2N Sodium hydroxide solution (20 mL) was added to the filtrate and the mixture was extracted three times with 50 mL ethyl acetate. Organic phases were pooled, dried with magnesium sulfate and evaporated.
  • the intermediate free piperazine was dissolved in N,N-dimethylformamide (10 mL) and potassium carbonate (166 mg, 1.20 mmol) and bromomethylcyclopropane (0.043 mL, 0.440 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 3 hours. Water (30 mL) was added and the mixture was extracted three times with 50 mL tert-butyl methylether. Organic phases were pooled, dried with magnesium sulfate and evaporated.
  • the intermediate free piperazine was dissolved in toluene (5 mL) and bromobenzene (0.084 mL, 0.80 mmol), sodium tert.-butylate (54 mg, 0.561 mmol), tris(dibenzylidenaceton)dipalladium (4 mg, 0.004 mmol) and rac-2,2'- bis(diphenylphosphino)-l,l'-binaphthyl (5 mg, 0.008 mmol) were added.
  • the reaction mixture was strirred at 80°C overnight. Water (20 mL) was added and the mixture was extracted three times with 20 mL ethyl acetate.
  • the active substance, lactose and corn starch are firstly mixed in a mixer and then in a comminuting machine.
  • the mixture is returned to the mixer, the talc is added thereto and mixed thoroughly.
  • the mixture is filled by machine into hard gelatine capsules.
  • the suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to 45°C. Thereupon, the finely powdered active substance is added thereto and stirred until it has dispersed completely. The mixture is poured into suppository moulds of suitable size, left to cool, the suppositories are then removed from the moulds and packed individually in wax paper or metal foil.
  • An injection solution may have the following composition and is manufactured in usual manner: Active substance 1.0 mg

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EP02710043A 2001-02-06 2002-01-28 Piperidinderivate als neurokinin 1 antagonisten Expired - Lifetime EP1360184B1 (de)

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DK02710043T DK1360184T3 (da) 2001-02-06 2002-01-28 Piperidinderivater som neurokinin-1-antagonister
EP02710043A EP1360184B1 (de) 2001-02-06 2002-01-28 Piperidinderivate als neurokinin 1 antagonisten

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EP01102557 2001-02-06
EP01102557 2001-02-06
EP02710043A EP1360184B1 (de) 2001-02-06 2002-01-28 Piperidinderivate als neurokinin 1 antagonisten
PCT/EP2002/000851 WO2002062784A1 (en) 2001-02-06 2002-01-28 Piperidinee derivatives as neurokinin 1 antagonists

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JO2696B1 (en) * 2002-12-23 2013-03-03 شركة جانسين فارماسوتيكا ان. في Derivatives of 1-piperdine-4-yl-4-biprolidine-3-yl-piperazine substituted and used as quinine antagonists
US7514424B2 (en) 2002-12-23 2009-04-07 Janssen Pharmaceutica N.V. Substituted 4-(4-piperidin-4-yl-piperazin-1-yl)-azepane derivatives and their use as neurokinin antagonists
JO2485B1 (en) * 2002-12-23 2009-01-20 شركة جانسين فارماسوتيكا ان. في 1-Piperidine-3-Yl-4-Piperidine-4-Yl-Piperazine derivatives substituted and used as quinine antagonists
ES2282731T3 (es) 2002-12-23 2007-10-16 Janssen Pharmaceutica N.V. Derivados de 1-piperidin-4-il-4-azetidin-3-il-piperazina sustituida y su uso como antagonistas de neuroquininas.
AU2004246817A1 (en) 2003-06-10 2004-12-23 Janssen Pharmaceutica N.V. Substituted 1, 4-di-piperidin-4-yl-piperazine derivative combined with an opioid analgesic and their use for the treatment of pain and side-effects associated with opioid-based treatments
JO2525B1 (en) * 2004-04-08 2010-03-17 شركة جانسين فارماسوتيكا ان. في Derived 4-alkyl-and-4-canoelperidine derivatives and their use as anti-neroquin
US7880002B2 (en) * 2004-12-29 2011-02-01 Millennium Pharmaceuticals, Inc. Substituted piperazinyl-pyrrolidine compounds useful as chemokine receptor antagonists
US7635698B2 (en) * 2004-12-29 2009-12-22 Millennium Pharmaceuticals, Inc. Compounds useful as chemokine receptor antagonists
EP1858888B1 (de) * 2005-02-16 2013-04-17 Merck Sharp & Dohme Corp. Heteroaryl-substituierte pyrazinyl-piperazin-piperidine mit cxcr3-antagonistischer aktivität
KR20070094666A (ko) 2005-02-25 2007-09-20 에프. 호프만-라 로슈 아게 약제 물질 분산성이 향상된 정제
US8604200B2 (en) * 2005-03-08 2013-12-10 Janssen Pharmaceutica N.V. Diaza-spiro-{4,4}-nonane derivatives as neurokinin (NK1) antagonists
AU2006292598B2 (en) 2005-09-16 2012-06-21 Janssen Pharmaceutica N.V. Cyclopropyl amines as modulators of the histamine H3 receptor
WO2007053499A2 (en) 2005-11-01 2007-05-10 Millennium Pharmaceuticals, Inc. Compounds useful as antagonists of ccr2
US8067457B2 (en) 2005-11-01 2011-11-29 Millennium Pharmaceuticals, Inc. Compounds useful as antagonists of CCR2
NZ577603A (en) 2006-12-14 2012-04-27 Janssen Pharmaceutica Nv Process for the preparation of piperazinyl and diazepanyl benzamide derivatives
EP2117538A1 (de) 2007-01-24 2009-11-18 Glaxo Group Limited Pharmazeutische zusammensetzungen mit 2-methoxy-5- (5-trifluoromethyl-tetrazol-i-yl-benzyl) - (2s-phenyl-piperidin-3s-yl-)
US8063075B2 (en) * 2008-06-10 2011-11-22 Hoffmann-La Roche Inc. Pyrrolidine ether derivatives as NK3 receptor antagonists
WO2010081851A1 (en) 2009-01-14 2010-07-22 Genoscience Pharma Piperidin-4-ylpiperazine compounds for the treatment of hcv infection
EP2729147B1 (de) 2011-07-04 2017-09-06 IRBM - Science Park S.p.A. Nk-1 rezeptorantagonisten zur behandlung der hornhautrevaskularisierung
JP2021514976A (ja) 2018-02-26 2021-06-17 オスペダーレ・サン・ラッファエーレ・エッセエッレエッレ 眼痛の治療における使用のためのｎｋ−１拮抗薬

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US6642226B2 (en) 2003-11-04
WO2002062784A8 (en) 2002-10-03
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CA2435946C (en) 2008-10-07
WO2002062784A1 (en) 2002-08-15
MXPA03006991A (es) 2003-11-18
DE60203481T2 (de) 2006-02-16
JP2004525892A (ja) 2004-08-26
CN1229373C (zh) 2005-11-30
CN1491222A (zh) 2004-04-21
ATE292128T1 (de) 2005-04-15
AU2002228072B2 (en) 2006-08-03
KR100566470B1 (ko) 2006-03-31
EP1360184B1 (de) 2005-03-30
KR20030070619A (ko) 2003-08-30
JP4181409B2 (ja) 2008-11-12
ZA200305887B (en) 2005-01-26
BR0206915A (pt) 2004-02-03
ES2238560T3 (es) 2005-09-01
DE60203481D1 (de) 2005-05-04
CA2435946A1 (en) 2002-08-15
DK1360184T3 (da) 2005-08-01
AR035427A1 (es) 2004-05-26

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